ML-007 / MapLight Therap - LARVOL DELTA

Comparative activity of muscarinic agonists ML-007 and xanomeline in preclinical models of psychosis and cognitive impairment (Neuroscience 2025) - "Both xanomeline and ML-007 show robust antipsychotic activity across a range of preclinical models for schizophrenia, including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response. Importantly, in a transgenic mouse model of Alzheimer's disease, we find that ML-007, but not xanomeline, improves hippocampal-dependent spatial memory task performance. Taken together, our data suggest that both M1 and M4 receptors contribute to antipsychotic activity in preclinical rodent models of psychosis, whereas strong agonism at M1 receptors may be required for treating cognitive impairment."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Enhancement of cognition in preclinical models by novel investigational M1/M4 agonist, ML-007 (ECNP 2025) - "Dose response testing of ML-007 revealed robust antipsychotic activity across a range of classical preclinical models of psychosis including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response (p<0.0001, 1-way ANOVA followed by Dunnett's multiple comparisons test, n=16 per group). Further consistent with the hypothesis that cognitive improvement is driven by strong activation of M1, the M4-selective positive allosteric modulator, emraclidine, was found to be inactive in the Y-maze memory assay. Together these studies suggest that M1 activity is critical for cognition in rodent models and that ML-007, due to its higher intrinsic activity at M1 receptors, could be ideally suited to address cognitive symptoms, in addition to treatment of psychosis in AD and schizophrenia."

Preclinical • Alzheimer's Disease • CNS Disorders • Psychiatry • Schizophrenia

Preclinical efficacy of the muscarinic agonist ML-007 in psychosis models depends on both M1 and M4 receptors. (PubMed, Neuropsychopharmacology) - "ML-007 is a potent brain-penetrant agonist at both M1 and M4 muscarinic receptors that has demonstrated compelling efficacy across a range of preclinical models of psychosis in schizophrenia including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response. Dose-response experiments in M1 and M4 knockout mice reveal that the efficacy of ML-007 is dependent on both M1 and M4 receptors. Taken together, our data suggest that both M1 and M4 receptors contribute to the potent efficacy of ML-007 in preclinical rodent models of psychosis."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Psychiatry • Schizophrenia

Comparative Activity of Muscarinic Agonists ML-007 and Xanomeline on Cognition and Psychosis in Preclinical Models of Schizophrenia and Alzheimer’s Disease (AAIC 2024) - "Amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response were used to assess potential antipsychotic activity of muscarinic agonists. Taken together, our data suggest that both M1 and M4 receptors contribute to antipsychotic activity in preclinical rodent models of schizophrenia, whereas strong agonism at M1 receptors may be required for treating cognitive impairment."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Comparative Activity of Muscarinic Agonists ML-007 and Xanomeline in Preclinical Models of Schizophrenia and Cognitive Impairment (ASCP 2024) - "Both xanomeline and ML-007 show robust antipsychotic activity across a range of preclinical models for schizophrenia, including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response. Learning Objectives Understand the relative contribution of M1 and M4 receptors to the antipsychotic and cognitive efficacy of muscarinic agonists. Understand that strong M1 agonism is required for pro-cognitive effects in a preclinical model of Alzheimer's disease."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

MAPLIGHT THERAPEUTICS ANNOUNCES COMPLETION OF PHASE 1 CLINICAL TRIAL FOR NOVEL M1/M4 MUSCARINIC AGONIST IN DEVELOPMENT FOR SCHIZOPHRENIA AND ALZHEIMER’S DISEASE PSYCHOSIS (PRNewswire) - P1 | N=NA | "MapLight Therapeutics...announced completion of a Phase 1 clinical trial evaluating the bioavailability, safety, and tolerability of an extended release formulation of ML-007, a novel M1/M4 preferring muscarinic agonist, alone and when co-administered with a precision-matched muscarinic antagonist designed to offset peripheral effects....Extended-release ML-007 was well tolerated in this trial at all doses, including those planned for use in the company's upcoming Phase 2 clinical trials for the treatment of schizophrenia and Alzheimer's disease psychosis. Plasma exposures at or above anticipated clinically relevant levels were maintained over the duration of the intended dosing interval....Findings from this study will enable formulation optimization of ML-007C-MA, the fixed-dose combination of ML-007 and its matched muscarinic antagonist, allowing the company to move ML-007C-MA into Phase 2 clinical trials later this year."

New P2 trial • P1 data • Alzheimer's Disease • CNS Disorders • Schizophrenia